Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis

Abstract

Objective. Imatinib is a small-molecule tyrosine kinase inhibitor capable of selective, dual inhibition of the transforming growth factor ␤ and platelet-derived growth factor (PDGF) pathways. Imatinib has previously been shown to prevent the development of inflammation-driven experimental fibrosis when treatment was initiated before administration of the profibrotic stimulus. The aim of this study was to confirm the efficacy of imatinib in a murine model of systemic sclerosis (SSc) that is less driven by inflammation and to investigate whether imatinib is also effective for the treatment of established fibrosis.Methods. The tight skin 1 (TSK-1) mouse model of SSc was used to evaluate the antifibrotic effects of imatinib in a genetic model of the later stages of SSc. In addition, the efficacy of imatinib for the treatment of preestablished fibrosis was analyzed in a modified model of bleomycin-induced dermal fibrosis in which the application of bleomycin was prolonged and the onset of treatment was late.Results. Treatment with imatinib reduced dermal and hypodermal thickening in TSK-1 mice and prevented the differentiation of resting fibroblasts into myofibroblasts. In the model of preestablished dermal fibrosis, imatinib not only stopped further progression of fibrosis but also induced regression of preexisting dermal fibrosis, with a reduction in dermal thickness below pretreatment levels.Conclusion. These results indicate that combined inhibition of the tyrosine kinase c-Abl and PDGF receptor might be effective in the later, less inflammatory stages of SSc and for the treatment of established fibrosis. Thus, imatinib might be an interesting candidate for clinical trials in patients with longstanding disease and preexisting tissue fibrosis.

Imatinib is effective for prevention and improvement of fibrotic fasciitis as a manifestation of chronic GVHD

“…Akhmetshina et al reported that imatinib was effective for treating fibrosis, as established in a mouse model of systemic sclerosis. 8 Our pathological findings show that imatinib resolved completed fibrosis in humans. Although we determined the starting dose of imatinib as 400 mg, smaller doses may be sufficient.…”

Imatinib: a novel treatment approach for generalized morphea

“…5,6,[8][9][10] Despite the fact that imatinib's antifibrotic mechanism is not completely known, Akhmetshina et al 4 concluded that imatinib might induce regression of fibrosis via its inhibitory effects on collagen synthesis, leading to a relative increase in matrix degradation, rather than by exerting direct effects on matrix degradation. Mild to moderate severity of superficial edema, most commonly on the eyelids, is reported in 48-65% of patients treated with imatinib.…”

“…3 Recent studies suggest imatinib's efficacy in the prevention and regression of fibrosis associated with systemic sclerosis, 3-6 nephrogenic sclerosis, 7 and bleomycin-related fibrosis. 4 …”

The origin of the myofibroblast in fibroproliferative vasculopathy: Does the endothelial cell steer the pathophysiology of systemic sclerosis?

“…Indeed, EndoMT might substantially contribute not only to pathologic vascular remodeling in SSc, but also to dermal and internal organ fibrosis, as has recently been observed in experimental models of kidney and lung fibrosis (13,15). Previous studies have shown that blocking of c-Abl with imatinib mesylate could prevent, or induce regression of, dermal fibrosis in different mouse models of SSc and could attenuate bleomycin-induced pulmonary fibrosis in mice (24)(25)(26). However, whether these effects would depend on the abrogation or reversal of the EndoMT process is unknown.…”